Faculty Bibliography

OBJECTIVES/OBJECTIVE:To analyze trends in the prevalence of medical complications in aneurysmal subarachnoid hemorrhage (aSAH) hospitalizations in the USA over the last decade. METHODS:A serial cross-sectional study was performed using the 2006-2022 National Inpatient Sample. Adult (≥ 18 years) primary aSAH hospitalizations with and without complications were identified using International Classification of Diseases codes. Negative binomial regression models were used to evaluate the associations between complications, individualized hospitalization characteristics, and hospital outcomes. RESULTS:Of 163,349 aSAH hospitalizations over the study period, 68.2% were female. The mean age was 55.6 years, and this increased over time (p-trend < 0.001). The mean National Inpatient Sample Subarachnoid Severity Score was 5.5 [standard error (SE) 0.06] and this also increased over time. Overall, 42.4% of hospitalizations had ≥ 1 medical complication. Urinary tract infections (UTI) (19.4%), pneumonia (15.4%), and sepsis (8.0%) were the most prevalent complications, while acute renal failure (ARF) (7.8%) was the most frequent noninfectious complication. The age- and sex-standardized prevalence of any medical complication remained stable over this study period, but there was marked heterogeneity in prevalence trends by complication type. ARF prevalence increased by nearly 300% [prevalence rate ratio (PRR): 1.04 per year, 95% confidence interval (CI): 1.02-1.04, p < 0.001] and deep venous thrombosis (DVT) prevalence increased by more than 200% (PRR:1.03, 95% CI: 1.01-1.04, p < 0.001) per year, while UTI and sepsis prevalence declined over this time (all p-trend < 0.001). Pneumonia prevalence declined in male only (p-trend < 0.05). Clipping was associated with higher DVT risk (PRR 1.24, 95% CI: 1.13-1.37) but lower gastrointestinal bleeding risk (PRR 1.14, 95% CI: 0.95-1.38) compared with coiling. All complications were significantly linked to poor outcomes (e.g., pneumonia: PRR 1.23, 95% CI: 1.20-1.30). CONCLUSIONS:The prevalence of infectious complications in aSAH has declined over the last decade, but this has been counterbalanced by a troubling increase in ARF and DVT prevalence. Given the strong association of all complications with poor outcomes, future studies focused on mitigating the prevalence of complications are needed to help improve aSAH outcomes.

OBJECTIVES/OBJECTIVE:To examine the effects of PlayReadVIP, a pediatric primary care intervention promoting early relational health, on child behaviors. STUDY DESIGN/METHODS:A factorial randomized controlled trial enrolled mother-child dyads postpartum. PlayReadVIP was delivered in two phases: birth to 3 years (PlayReadVIP 0-3) and 3 to 5 years (PlayReadVIP 3-5). At enrollment, dyads were assigned to PlayReadVIP 0-3 or control. At age 3, dyads were re-randomized to PlayReadVIP 3-5 or control. Analyses included dyads with a second randomization and complete data on the mediators and child outcomes. In PlayReadVIP, dyads attended one-on-one sessions with a parent coach, in which they received child development information, learning materials, and real-time, strengths-based feedback on brief video recordings of parent-child interactions. Cognitive stimulation and harsh discipline were reported by mothers. Child behaviors were assessed using the Behavior Assessment System for Children, Second Edition. RESULTS:grade. No significant indirect effects through harsh discipline were found. CONCLUSIONS:PlayReadVIP leads to sustained but small improvements in child behaviors by enhancing maternal cognitive stimulation, emphasizing the potential of early intervention in pediatric primary care for promoting child mental health in disadvantaged populations.

The gut microbiota can affect neuronal excitability, inflammation, and oxidative balance via the gut-brain axis, shaping seizure susceptibility. To translate these findings into clinical approaches, a synthesis of preclinical microbiome-based evidence is needed. This systematic review and meta-analysis examined the putative anticonvulsant, anti-inflammatory, antioxidant, and neuroprotective effects of probiotics in rodent models. An extensive systematic search up to July 2025 identified eligible animal studies in which probiotics were administered in seizure models. Reported outcomes included seizure latency, duration, severity, and frequency, as well as inflammation, oxidative stress, and behavioral measures. Of the 24 studies that met the inclusion criteria, 19 provided sufficient data to be included in the meta-analysis. The most frequently used strains belonged to the Lactobacillus (e.g., acidophilus, casei, fermentum) and Bifidobacterium genera (e.g., bifidum, longum), with occasional synbiotic combinations. Probiotics significantly increased seizure latency (MD = 22.09; 95 % CI: 10.52 to 33.67) and reduced seizure severity (MD = -1.08; 95 % CI: -1.39 to -0.76) and duration (MD = -23.19; 95 % CI: -35.56 to -10.82). Probiotics significantly reduced IL-1β, IL-6, and TNF-α levels while MDA showed a nonsignificant trend toward reduction (p = 0.076). Behaviorally, improvements in spatial learning (p < 0.05) and reduced anxiety-like behavior (p < 0.001) were observed. Probiotic supplementation appears to exert anticonvulsant, anti-inflammatory, antioxidant, and behavioral benefits in preclinical epilepsy models, although the evidence is heterogeneous and limited to animal studies. Mechanistic evidence indicates modulation of the gut-brain axis, enhanced GABAergic signaling, and improved mitochondrial function. These findings support further investigation of specific probiotic formulations as promising adjunct candidates in well-designed, mechanism-driven clinical trials.

OBJECTIVE/UNASSIGNED:The authors sought to examine substance use patterns across the sexual identity spectrum, particularly among individuals who describe their sexual identity using different terms or express uncertainty about their orientation-groups that remain poorly understood beyond lesbian, gay, or bisexual (LGB) categories. METHODS/UNASSIGNED:Using data from the 2023 National Survey on Drug Use and Health among individuals ≥12 years of age (N=52,525), the authors examined past-year substance use across five sexual identity groups: heterosexual, gay/lesbian, bisexual, those using a different term to describe their sexual identity, and those unsure of their identity. Associations were examined between sexual identity (overall and disaggregated by sex using sex-specific heterosexual reference groups) and past-year use of cannabis, hallucinogens, cocaine, inhalants, methamphetamine, and misuse of prescription opioids, tranquilizers/sedatives, and stimulants. RESULTS/UNASSIGNED:Substance use was higher across all other sexual identity groups compared with heterosexual individuals. Bisexual and gay/lesbian individuals showed elevated odds across most substances examined, particularly inhalants, hallucinogens, and cannabis. Both individuals using different terms and those unsure of their sexual identity showed elevated odds for inhalants, hallucinogens, cannabis, and prescription tranquilizer/sedative misuse, with those using different terms additionally showing elevated odds for prescription stimulant misuse. In sex-disaggregated analyses, both males and females showed elevated odds across multiple substances, with females generally showing elevations across a greater number of substances, although some estimates for males were suppressed due to small sample sizes. CONCLUSIONS/UNASSIGNED:These findings extend our understanding of substance use beyond LGB categories, revealing nuanced patterns among emerging identity groups, underscoring the importance of targeted screening and prevention strategies.

PURPOSE/UNASSIGNED:We sought to determine whether combining prostate health index (Phi) with urinary prostate cancer antigen 3 (PCA3) and TMPRSS2:ERG (T2:ERG) could improve selection of men for prostate biopsy. These biomarkers have been validated in prostate cancer (PCa) detection separately, but their combination has not previously been developed. MATERIALS AND METHODS/UNASSIGNED:values were obtained through bootstrap in the validation study. RESULTS/UNASSIGNED:= .002). CONCLUSIONS/UNASSIGNED:Combining serum Phi with urinary PCA3 RNA alone or together with urinary T2:ERG RNA, simultaneously or sequentially, improves selection of men for initial prostate biopsy and represents an avenue to improve early detection of aggressive PCa.

Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy¹. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth^2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.

INTRODUCTION/BACKGROUND:As total hip arthroplasty and total knee arthroplasty procedures are increasingly performed on younger patients with obesity, the optimal approach to preoperative weight management remains undefined. This study explores national trends among US arthroplasty surgeons regarding body mass index (BMI) cutoffs, weight optimization strategies, and weight loss medication usage. METHODS:A 28-question national survey was distributed through e-mail to members of the American Association of Hip and Knee Surgeons and shared on professional social media platforms (Facebook, ResearchGate, and LinkedIn) between January 1 and August 5, 2024. RESULTS:Regarding arthroplasty reconstruction fellowship training, 82.58% (441/534) of respondents were fellowship trained, 11.42% (61/534) were not fellowship trained, and 5.99% (32/534) trained in other specialties. In terms of BMI optimization strategies, 82.84% (n = 444/536) recommended structured diet and exercise programs, 77.99% (n = 418/536) recommended dietitian or weight loss specialist programs, and 52.61% (n = 282/536) advocated for bariatric surgery. For total hip arthroplasty, 45.13% of surgeons used a BMI cutoff <40 kg/m2 (n = 241/534), followed by 23.97% advocating for no strict cutoff (n = 128/534). For total knee arthroplasty, 41.65% reported using a cutoff of <40 kg/m2 (n = 222/533), with 24.39% (n = 130/533) reporting no strict BMI cutoff. In addition, 27.62% (n = 58/210) reported that their patients used weight loss medications such as GLP-1 agonists. Notably, 68.0% (n = 356/526) of surgeons allowed up to 1 to 2 years for BMI optimization before surgery. CONCLUSION/CONCLUSIONS:Although many arthroplasty surgeons use BMI cutoffs, many accommodate patients through nonsurgical interventions to facilitate weight loss. These findings indicate that many respondents report a multidisciplinary approach to preoperative BMI optimization.

Autophagy, a programmed self-eating process, underlies the progression of multifactorial diseases like pancreatic ductal adenocarcinoma (PDA). Except for nutrient availability, the contribution of microenvironmental factors to autophagy regulation is not well understood. Through integrating functional genomics and tumor-like 3D cultures, we show that human PDA cells regulate their autophagy levels by sensing the extracellular matrix (ECM) via the integrinα3-Hippo-YAP1 axis. The spatial proximity of PDA cells to the ECM shapes their intracellular autophagy levels, leading to heterogeneous biological responses. Specifically, PDA cells with low autophagy levels are proliferative, whereas those with high autophagy levels display better tolerance to chemotherapies. Targeting the ECM-mediated autophagy regulation reduces autophagic heterogeneity, alters PDA growth, and shapes antitumor responses to FDA-approved therapies. In summary, we have characterized a non-metabolic regulation of autophagy through ECM sensing, opening the possibility to investigate and target ECM-specific outputs in diseases.

STUDY DESIGN/METHODS:Cohort study of pooled data from patients enrolled in a behavior randomized trial (RCT) that successfully increased physical activity after complex lumbar surgery. OBJECTIVE:To assess associations between increased energy expenditure from walking and general functional status and lumbar-specific disability 12 months after enrollment. BACKGROUND:Many postoperative patients retain preoperative sedentary lifestyles and thus do not obtain general health and spine-related benefits of physical activity. METHODS:Three months after complex lumbar surgery (i.e. fusion, ≥3 levels) patients were enrolled in a behavior RCT aimed at increasing physical activity from walking measured by the Paffenbarger Physical Activity and Exercise Index (PAEI) in kcals/week. Data were pooled for this analysis to assess associations between kcals/week at 12 months and change in general functional status (RAND 12-Item Physical Component Summary score, PCS) and lumbar-specific disability (Oswestry Disability Index, ODI). Covariates considered included age, sex, body mass index, back pain, surgical complexity, depressive symptoms, and enrollment PCS, ODI and kcals/week. RESULTS:Among 231 patients (mean age 64, 47% women) enrollment walking was 1361±1294 kcals/week and increased to 1935±1979 kcals/week at 12 months, mean within-patient change 574 kcals/week (P<.0001). Enrollment PCS score was 37±10 and improved to 44±11 at 12 months, exceeding a clinically important difference (CID). Change in PCS score was associated with kcals/week at 12 months in multivariable analysis controlling for enrollment kcals/week and PCS score (coefficient .002, 95% CI .001-.003, P<.0001). Enrollment ODI score was 34±16 and improved to 27±19 at 12 months, exceeding a CID. Change in ODI score was associated with kcals/week at 12 months in multivariable analysis controlling for enrollment kcals/week and ODI score (coefficient .01, 95% CI 0.002-.005, P<0.0001). CONCLUSIONS:Increased postoperative energy expenditure from walking at 12 months was associated with improvement in general functional status and reduced lumbar-specific disability in patients after complex lumbar surgery.

Centromeres ensure accurate chromosome segregation, yet their DNA evolves rapidly across eukaryotes leaving the origins of new centromere architectures unclear^1-4. The brewer's yeast Saccharomyces cerevisiae exemplifies this long-standing puzzle. Its centromeres shifted ancestrally from large, repeat-rich, epigenetically specified forms to the compact, genetically defined 'point' centromeres^1,5. How this transition occurred has remained unresolved⁶. Here we identify evolutionarily related 'proto-point' centromeres that provide a resolution to the evolutionary origins of point centromeres. Proto-point centromeres contain a single centromeric nucleosome positioned over an AT-rich core, accompanied by relaxed organization and sequence variability of flanking cis-elements. In two species, these proto-point centromeres lie within retrotransposon-derived repeat clusters, linking ancestral repeat-rich centromeres to genetically encoded ones. Comparative and phylogenetic analyses indicate that proto-point and point centromeres evolved in an ancestor with retrotransposon-rich centromeres. These results identify long-terminal-repeat retrotransposons, specifically Ty5 sequences, as the genetic substrate for point-centromere evolution and provide a mechanistic route by which an epigenetic centromere can become genetically specified. More broadly, they show how selfish elements can be co-opted to perform essential chromosomal functions.